Dataset Information

Structural basis for ligand recognition of the neuropeptide Y Y₂ receptor.

ABSTRACT: The human neuropeptide Y (NPY) Y₂ receptor (Y₂R) plays essential roles in food intake, bone formation and mood regulation, and has been considered an important drug target for obesity and anxiety. However, development of drugs targeting Y₂R remains challenging with no success in clinical application yet. Here, we report the crystal structure of Y₂R bound to a selective antagonist JNJ-31020028 at 2.8?Å resolution. The structure reveals molecular details of the ligand-binding mode of Y₂R. Combined with mutagenesis studies, the Y₂R structure provides insights into key factors that define antagonistic activity of diverse antagonists. Comparison with the previously determined antagonist-bound Y₁R structures identified receptor-ligand interactions that play different roles in modulating receptor activation and mediating ligand selectivity. These findings deepen our understanding about molecular mechanisms of ligand recognition and subtype specificity of NPY receptors, and would enable structure-based drug design.

SUBMITTER: Tang T

PROVIDER: S-EPMC7854658 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Structural basis for ligand recognition of the neuropeptide Y Y2 receptor.

Tang Tingting T Hartig Christin C Chen Qiuru Q Zhao Wenli W Kaiser Anette A Zhang Xuefeng X Zhang Hui H Qu Honge H Yi Cuiying C Ma Limin L Han Shuo S Zhao Qiang Q Beck-Sickinger Annette G AG Wu Beili B

Nature communications 20210202 1

The human neuropeptide Y (NPY) Y2 receptor (Y2R) plays essential roles in food intake, bone formation and mood regulation, and has been considered an important drug target for obesity and anxiety. However, development of drugs targeting Y2R remains challenging with no success in clinical application yet. Here, we report the crystal structure of Y2R bound to a selective antagonist JNJ-31020028 at 2.8 Å resolution. The structure reveals molecular details ...[more]

PMID: 33531491

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Project description:Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms1 by synchronization to environmental cues and is involved in diverse physiological processes2 such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function3. Melatonin is formed in the pineal gland in a light-regulated manner4 by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT1) and type 1B (MT2)3,6. Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden7. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids8,9, and is one of the most popular supplements in the United States10. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT1 in complex with four agonists: the insomnia drug ramelteon11, two melatonin analogues, and the mixed melatonin-serotonin antidepressant agomelatine12,13. The structure of MT2 is described in an accompanying paper14. Although the MT1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors.

Dataset Information

Structural basis for ligand recognition of the neuropeptide Y Y₂ receptor.

Publications

Structural basis for ligand recognition of the neuropeptide Y Y<sub>2</sub> receptor.

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